Chronic myelogenous leukemia Philadelphia chromosome

Explain the role of the Philadelphia chromosome in the pathophysiology of chronic myelogenous leukemia (CML). 

A well-known use of molecular methods is in the study of chromosomal translocations. Thus, in Philadelphia chromosome (ph1) positive chronic myelogenous leukemia (CML), the C-abl oncogene on chromosome 9 is translocated to a region on chromosome 22 called the breakpoint cluster region, or bcr. This (t9 22) translocation results in production of an abnormal fusion protein... 

Cytogenetic analysis of patients with chronic myelogenous leukemia (CML) reveals an unusual translocation between chromosomes 9 and22 termed the Philadelphia chromosome."... 

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

Indications Treatment of chronic hepatitis C, hairy-cell leukemia and AIDS-related Kaposi s sarcoma, as well as for the treatment of chronic phase, Philadelphia chromosome-positive chronic myelogenous leukemia (CML)... 

Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210BCR/ABL gene of the Philadelphia chromosome. Science 1990 247 824-830. 

Quintas-Cardama A, Kantarjian H, Jones Det al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure, fi/ooct 2007 109 497M99. 

The first chromosome abnormality found to be associated with a cancer was the Philadelphia chromosome, which arises as a result of a reciprocal translocation between chromosomes 9 and 22 (fig. S4.4). The tumor associated with this translocation is chronic myelogenous leukemia and results from the activation of the c-abl oncogene, which is normally located on chromosome 9. 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

Hazarika M et al (2008) Tasigna for chronic and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 14 5325-5331... 

Imatinib. Chronic myelogenous leukemia (CML) results from a genetic defect in the hematopoietic stem cells of the bone marrow. Nearly all CML patients possess the Philadelphia chromosome. It results from translocation between chromosomes 9 and 22 of the c-abl protooncogene, leading to the hybrid bcr-abl fusion gene on chromosome 22. The recombinant gene encodes a tyrosine kinase mutant with unregulated (constitutive), enhanced activity that promotes cell proliferation. Imatinib is a tyrosine kinase inhibitor that specifically affects this mutant but also interacts with some other kinases. It can be used orally in Philadelphia chromo-some-positive CML. 

Neviani P, Santhanam R, Oaks JJ, Hiring AM, Notari M, Blaser BW, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J. Clin. Invest. 2007 117 2408-2421. 

Kantarjian HM, O Brien S, Smith TL, Rios MB, Cortes J, Beran M, Koller C, Giles FJ, Andreeff M, Kornblau S, Giralt S, Keating MJ, Talpaz M. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol 1999 17(l) 284-92. 

Chronic myelogenous leukemia results from a reciprocal translocation between chromosomes 9 and 22, which forms the Philadelphia chromosome (Ph+). This chromosomal... 

Johnson JR, Bross P, Cohen M, et al. Approval summary Imatinib mesylate capsules for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Clin Cancer Res 2003 9 1972-1979. 

ANLL, acute nonlymphocytic leukemia APE, acute promyelocytic leukemia CEL, chronic lymphocytic leukemia CML, chronic myelogenous leukemia EGER, epidermal growth factor receptor CIST, gastrointestinal stromal tumor MoAB, monoclonal antibody NE-kB, nuclear factor-KB Ph+ ALL, Philadelphia chromosome-positive acute lymphocytic leukemia PCP, Pneumocystis carinii pneumonia WBC, white blood cell. 

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved for treatment of cancer (see Table 124—18). It inhibits deregulated bcr-abl tyrosine kinase, the molecular abnormality in patients with chronic myelogenous leukemia that results from the characteristic Philadelphia chromosome translocation. The deregulated tyrosine kinase constantly drives leukemic cell proliferation. Imatinib inhibits cell proliferation and induces apoptosis in the Philadelphia chromosome-positive cells. It is relatively, but not completely, selective for these cells. °°... 

FIGURE 132-1. Diagram of the chromosomal translocation that results in the Philadelphia chromosome. This abnormality is encountered in 90% to 95% of patients who have chronic myelogenous leukemia. (From Fishleder AK. Oncogenes and cancer clinical applications. Cleve Clin J Med 1990 57 721-726.)... 

Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of chronic myelogenous leukemia and acute lymphocytic leukemia with the Philadelphia chromosome. NEngl J Med 2001 344 1038-1042. 

Kantarjian H, Talpaz M, O Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myelogenous leukemia. Blood 2004 103 2873-2878. 

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